1. Field of the Invention
The present invention relates to the use of particular adenosine A1 agonists belonging to a class of N6-substituted-5xe2x80x2-(N-substituted) carboxamidoadenosines in the treatment of heart rhythm disturbances in mammals, and to novel dosage forms for practicing this new use.
2. Related Art
In the mammalian heart, in order to circulate blood, contraction of the ventricles is initiated by an electrical impulse in the sinoatrial (SA) node that then passes through the atrioventricular (AV) node to the ventricles. Consistent rhythmic impulses produce a regular heart beat when the heart is functioning normally.
Various dysfunctions can occur in the heart to disturb the regular heart beat pattern and produce arrhythmias. For example, a condition of excessively rapid heart beats can occur that is defined as tachycardia. Tachycardia can originate from excessively rapid discharges from a malfunctioning SA node, electrical impulses passing through accessory pathways that prompt beats before they would normally occur, or re-entry of impulses in the AV node. In such cases, the disorder has been referred to as paroxsymal supraventricular tachycardia (PSVT), which in some patients can progress to congestive heart failure. Another heart rhythm disturbance, referred to as atrial fibrillation/flutter (AF), is characterized by a rapid and disordered beating of the atria, and is associated with an increased incidence of stroke. The above described heart rhythm disturbances can be classified as supraventricular tachyarrhythmias. Symptoms of these disorders can include discomfort due to palpitations, fatigue, dyspnea, as well as a sensation of lightheadedness and/or dizziness.
Adenosine is well-known to slow heart rate (negative chronotropic effect) and slow impulse conduction through the AV node (negative dromotropic effect) (Berne et al., U.S. Pat. No. 4,673,563; Belardinelli et al., Journal of Pharmacology and Experimental Therapeutics 271: 1371(1994)). Adenosine is currently used in the treatment of PSVT, but it has not proven efficacious in converting AF to normal sinus rhythm.
Adenosine acts through multiple receptor subtypes, termed A1, A2A, A2B, and A3. The adenosine A1 receptor mediates adenosine""s negative chronotropic and negative dromotropic effects as well as directly depressing atrial (but not ventricular) contractility. The adenosine A2A receptor mediates adenosine""s action of dilating coronary arteries. The localization and function of adenosine A2B and A3 receptors in the heart have not been well defined.
Since PSVT can result from abnormally frequent impulses affecting the AV node and since the adenosine A1 receptor mediates adenosine""s negative dromotropic effect, one strategy to terminate PSVT is to use a selective adenosine A1 receptor agonist to slow impulse conduction through the AV node (Belardinelli et al., Journal of Pharmacology and Experimental Therapeutics 271: 1371 (1994); Snowdy et al., British Journal of Pharmacology 126: 137 (999)).
However, adenosine A1 receptor agonists that have been heretofore studied for this purpose lacked the necessary potency, selectivity, oral bioavailability and/or pharmacodynamic activity. In addition, prior art adenosine A1 agonists have also been shown to be hypotensive, a side effect that would worsen symptoms of patients experiencing heart rhythm disturbances.
A series of N6-substituted-5xe2x80x2-(N-substituted)carboxamidoadenosine derivatives have been previously described. These compounds are selective adenosine A1 receptor agonists (Olsson, R. and Thompson, R., U.S. Pat. No. 5,310,731), having utility as vasodilatory or anti-hypertensive agents.
The present invention is directed to a method for treatment of heart rhythm disturbances in a mammal that would benefit from the induction of negative dromotropic action, negative chronotropic action, or a combination thereof, comprising:
administering to a mammal in need of such treatment an effective amount of a compound of Formula I: 
xe2x80x83or a pharmaceutically acceptable salt or ester thereof, wherein
R1 is C3-7 secondary alkyl, C3-8 cycloalkyl, or C7 bicycloalkyl; and
R2 is C1-4 alkyl, C1-4 hydroxyalkyl or C3-5 cycloalkyl.
Such heart rhythm disturbances include supraventricular tachyarrhythmias, such as paroxysmal supraventricular tachycardia (PSVT) and atrial fibrillation/flutter (AF).
The present invention is also directed to novel intravenous and oral dosage forms comprising particular concentrations of one or more compounds of Formula I.
The present invention is also directed to the use of a compound of Formula I in the manufacture of a medicament for treating heart rhythm disturbances in a mammal that would benefit from the induction of negative dromotropic action, negative chronotropic action, or a combination thereof.